EP2358695B1 - Verfahren zur herstellung von zanamivir und zwischenprodukte zur verwendung in dem verfahren - Google Patents

Verfahren zur herstellung von zanamivir und zwischenprodukte zur verwendung in dem verfahren Download PDF

Info

Publication number
EP2358695B1
EP2358695B1 EP09756775.4A EP09756775A EP2358695B1 EP 2358695 B1 EP2358695 B1 EP 2358695B1 EP 09756775 A EP09756775 A EP 09756775A EP 2358695 B1 EP2358695 B1 EP 2358695B1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
preparing
zanamivir
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP09756775.4A
Other languages
English (en)
French (fr)
Other versions
EP2358695A2 (de
Inventor
Manjinder Singh Phull
Rajendra Narayanrao Kankan
Dharmaraj Ramachandra Rao
Ashwini Amol Sawant
Sanoj Thoppil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Ltd filed Critical Cipla Ltd
Priority to EP12161848.2A priority Critical patent/EP2476675A1/de
Publication of EP2358695A2 publication Critical patent/EP2358695A2/de
Application granted granted Critical
Publication of EP2358695B1 publication Critical patent/EP2358695B1/de
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring

Definitions

  • the present invention relates to an improved process for the preparation of a neuraminidase inhibitor. More particularly, the present invention relates to a process for the preparation of zanamivir and to novel intermediates for use in the process.
  • Zanamivir is the first neuraminidase inhibitor to be developed commercially, and it is used in the treatment of and prophylaxis of both Influenza virus A and Influenza virus B.
  • zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (Formula I), and is represented by the following structure:
  • Zanamivir binds to the conserved region of influenza neuraminidase enzyme, which mainly catalyzes the cleavage of terminal sialic acid attached to glycolipids and glycoproteins.
  • WO1994/07885 discloses a process for preparing zanamivir, as given in Scheme 2 below, by treating 5-acetamido-4-amino-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid (VI), obtained from WO1991/16320 , with cyanogen bromide in the presence of sodium acetate to yield 4-cyanoamide derivative (VII) which is further reacted with ammonium formate and ammonia.
  • VI 5-acetamido-4-amino-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid
  • AU672634 discloses the synthesis of zanamivir by reacting the 5-acetamido-4-amino-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylic acid (VI) with pyrazole-1H-carboxamidine.
  • EP0539204 also discloses the preparation of zanamivir by treating cyano derivative (VII) with an amine derivative or treating 4-amino compound (VI) with a carbamimidic compound.
  • EP0623121 discloses the use of a Lindlar catalyst (lead doped palladium catalyst) for the conversion of the methyl 5-acetamido-4-azido-2,3-didehydro-2,3,4,5-tetradeoxy-D-glycero-D-galacto-2-nonulopyranosidonate to its methyl 5-acetamido-4-amino-2,3-didehydro-2,3,4,5-tetradeoxy-D-glycero-D-galacto-2-nonulopyranosidonate form. It has been found that recovery of the Lindlar catalyst from the reactant solution requires an expensive procedure, thus making the process expensive. Also this catalyst has a short lifetime due to poisoning.
  • Douglas S. Johnson and Jie Jack Li “7. Neuraminidase inhibitors for influenza: oseltamivir phosphate and zanamivir"
  • Douglas S. Johnson and Jie Jack Li “The Art of Drug Synthesis", 6 July 2007, John Wiley and Sons, pages 95-114 discloses processes for the synthesis of zanamivir.
  • a process for preparing methyl 5-acetamido-4-amino-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate comprises reducing methyl 5-acetamido-4-azido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (IV) in the presence of a reducing agent, wherein the reducing agent is zinc/ammonium chloride.
  • the reducing agent is zinc dust/ammonium chloride.
  • a process for preparing a compound of formula (VIII) which process comprises preparing a compound (V) according to the first aspect of the invention and reacting compound of formula (V) with a cyanogen halide.
  • the cyanogen halide is cyanogen bromide.
  • a process for preparing a compound of formula (IX) which process comprises preparation of a compound (VIII) according to the process described above, and deacetylation of a compound of formula (VIII).
  • the deacetylating agent is selected from the group consisting of methanol/iodine, methanol/water, sodium t-butoxide, potassium carbonate, sodium hydroxide and sodium methoxide.
  • the deacetylating agent is sodium methoxide.
  • a process for preparing a compound of formula (VII) which process comprises preparing a compound of formula (IX) according to the process described above, and hydrolysing the ester group of a compound of formula (IX).
  • the hydrolysis takes place in the presence of an organic or inorganic base.
  • the organic base may be selected from the group consisting of pyridine, dimethylamine, trimethylamine and sodium ethoxide.
  • the inorganic base may be selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate and potassium bicarbonate.
  • a process for preparing zanamivir of formula (I) comprises preparing a compound of formula (VII) according to the process described above, and reacting the compound of formula (VII) with ammonium formate in presence of ammonia.
  • the ammonia is in the form of gaseous ammonia, liquid ammonia or aqueous ammonia.
  • the reaction of the compound (VII) to form zanamivir is carried out at a high temperature ranging from about 80°C to about 100°C.
  • the zanamivir is isolated as a solid.
  • the crude solid may be purified.
  • the process may further comprise recrystallising the crude zanamivir.
  • the solid product may be purified with water, an alcoholic solvent or mixtures thereof.
  • the purified zanamivir is typically produced having a high purity, for example a purity of 99.5% or higher, as determined by HPLC.
  • Zanamivir having purity greater than or equal to 99.5% is described herein.
  • Zanamivir prepared according to a process described above is described herein.
  • a pharmaceutical composition comprising zanamivir prepared according to a process described above together with one or more excipients is described herein.
  • zanamivir prepared according to a process described above in medicine is described herein.
  • Zanamivir prepared according to a process described above for use in the treatment or prophylaxis of Influenza virus A or Influenza virus B is described herein.
  • the present invention provides a process for preparing methyl 5-acetamido-4-amino-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate (V), as depicted in Scheme 3 below.
  • the reduction of the azide group to the corresponding amine group occurs under mild conditions and may be carried out at room temperature (for example 25°C - 35°C) due to the use of the milder reducing agent.
  • an important feature of, for example, zinc is that the process requires shorter time for completion as compared to the prior art processes.
  • the present invention provides a process for preparing zanamivir which process involves the use of novel intermediates VIII and IX, as depicted below in Scheme 4, wherein compound (V) is prepared according to Scheme 3.
  • the present invention provides a process for preparing zanamivir of formula I, which process comprises preparing a compound (V) according to Scheme 3 and:
  • the solid product may optionally be purified with water, an alcoholic solvent or mixtures thereof to obtain highly pure zanamivir having HPLC purity of 99.5% or higher.
  • the process for preparing zanamivir is carried out by isolating the intermediates obtained in the preceding steps.
  • the process of the present invention involves the use of zinc/ammonium chloride as the reducing agent which is a cheap and easily recoverable catalyst. Further, with the use of this catalyst, the time required for completion of reaction is shorter as compared to the prior art processes wherein about 4 to 16 hours are required for reduction to take place.
  • the process of the present invention is simple, economical, eco-friendly and industrially scaleable.
  • Step A Preparation of methyl 5-acetamido-4-amino-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate-compound (IV) to compound (V)
  • Step B Preparation of methyl 5-acetamido-4-cyanamido-6-(1,2,3-triacetoxyropyl)-5,6-dihydro-4H-pyran-2-carboxylate-compound (V) to compound (VIII)
  • Step C Preparation of methyl 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl)-5,6-dihydro-4H-pyran-2-carboxylate-compound (VIII) to compound (IX)
  • reaction mass from step B containing methanol was chilled to about 15°C and then sodium methoxide (3.1 g) was added at 10°C - 15°C. The reaction mass was stirred for 30 min at 20°C and was monitored. This reaction mass (7.6 g) was used in the next step of synthesis.
  • Step D Preparation of 5-acetamido-4-cyanamido-6-(1,2,3-trihydroxypropyl-5,6-dihydro-4H-pyran-2-carboxylic acid - compound (IX) to compound (VII)
  • reaction mass (7.6 g), from step C, in methanol was cooled to 15°C.
  • sodium hydroxide (0.9 g) in 30 ml water was added at 15°C and then stirred at 25°C for an hour.
  • 50ml water was charged and pH of the reaction mass was adjusted with amberlite cation resin to pH 6.5 - 7.
  • the resin was filtered, washed with deionised water and the filtrate was concentrated below 50°C to obtain a solid residue (7.3 g).
  • Step F Purification of zanamivir

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Claims (11)

  1. Verfahren zur Herstellung von 5-Acetamido-4-amino-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carbonsäuremethylester (V), wobei das Verfahren das Reduzieren von 5-Acetamido-4-azido-6-(1,2,3-triacetoxypropyl)-5,6-dihydro-4H-pyran-2-carbonsäuremethylester (IV) in Gegenwart eines Reduktionsmittels umfasst, wobei das Reduktionsmittel Zink/Ammoniumchlorid ist:
    Figure imgb0020
  2. Verfahren nach Anspruch 1, wobei das Reduktionsmittel Zinkstaub/Ammoniumchlorid ist.
  3. Verfahren zur Herstellung einer Verbindung der Formel (VIII), wobei das Verfahren das Herstellen einer Verbindung (V) nach Anspruch 1 oder 2 und das Umsetzen einer Verbindung der Formel (V) mit einem Cyanogenhalogenid der Formel N≡C-X umfasst, wobei X Fluor, Chlor, Brom oder Iod ist:
    Figure imgb0021
  4. Verfahren nach Anspruch 3, wobei das Cyanogenhalogenid Cyanogenbromid ist.
  5. Verfahren zur Herstellung einer Verbindung der Formel (IX), wobei das Verfahren die Herstellung einer Verbindung (VIII) nach Anspruch 3 oder 4 und die Deacetylierung einer Verbindung der Formel (VIII) in Gegenwart eines Deacetylierungsmittels umfasst:
    Figure imgb0022
  6. Verfahren nach Anspruch 5, wobei das Deacetylierungsmittel aus der Gruppe bestehend aus Methanol/Iod, Methanol/Wasser, Natriumtert.-butoxid, Kaliumcarbonat, Natriumhydroxid und Natriummethoxid ausgewählt ist.
  7. Verfahren zur Herstellung einer Verbindung der Formel (VII), wobei das Verfahren das Herstellen einer Verbindung der Formel (IX) nach Anspruch 5 oder 6 und das Hydrolysieren einer Verbindung der Formel (IX) umfasst:
    Figure imgb0023
  8. Verfahren nach Anspruch 7, wobei die Hydrolyse in Gegenwart einer organischen oder anorganischen Base stattfindet.
  9. Verfahren nach Anspruch 7 oder 8, wobei die Base aus der Gruppe bestehend aus Pyridin, Dimethylamin, Trimethylamin, Natriumethoxid, Natriumcarbonat, Kaliumcarbonat, Magnesiumcarbonat, Calciumcarbonat, Natriumhydrogencarbonat und Kaliumhydrogencarbonat ausgewählt ist.
  10. Verfahren zur Herstellung von Zanamivir, wobei das Verfahren das Herstellen einer Verbindung der Formel (VII) nach einem der Ansprüche 7 bis 9 und das Umsetzen der Verbindung der Formel (VII) mit Ammoniumformiat in Gegenwart von Ammoniak umfasst, um Zanamivir zu erhalten.
  11. Verfahren nach Anspruch 10, das weiterhin das Umkristallisieren des Zanamivirs umfasst.
EP09756775.4A 2008-11-28 2009-11-24 Verfahren zur herstellung von zanamivir und zwischenprodukte zur verwendung in dem verfahren Not-in-force EP2358695B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12161848.2A EP2476675A1 (de) 2008-11-28 2009-11-24 Verfahren zur Herstellung von Zanamivir und Zwischenprodukte zur Verwendung in dem Verfahren

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2502MU2008 2008-11-28
PCT/GB2009/002744 WO2010061182A2 (en) 2008-11-28 2009-11-24 Process for preparing zanamivir and intermediates for use in the process

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP12161848.2A Division-Into EP2476675A1 (de) 2008-11-28 2009-11-24 Verfahren zur Herstellung von Zanamivir und Zwischenprodukte zur Verwendung in dem Verfahren

Publications (2)

Publication Number Publication Date
EP2358695A2 EP2358695A2 (de) 2011-08-24
EP2358695B1 true EP2358695B1 (de) 2014-07-02

Family

ID=41693037

Family Applications (2)

Application Number Title Priority Date Filing Date
EP12161848.2A Withdrawn EP2476675A1 (de) 2008-11-28 2009-11-24 Verfahren zur Herstellung von Zanamivir und Zwischenprodukte zur Verwendung in dem Verfahren
EP09756775.4A Not-in-force EP2358695B1 (de) 2008-11-28 2009-11-24 Verfahren zur herstellung von zanamivir und zwischenprodukte zur verwendung in dem verfahren

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP12161848.2A Withdrawn EP2476675A1 (de) 2008-11-28 2009-11-24 Verfahren zur Herstellung von Zanamivir und Zwischenprodukte zur Verwendung in dem Verfahren

Country Status (9)

Country Link
US (1) US8993789B2 (de)
EP (2) EP2476675A1 (de)
JP (1) JP2012510456A (de)
KR (1) KR20110098760A (de)
AU (1) AU2009321347A1 (de)
CA (1) CA2744793A1 (de)
ES (1) ES2507492T3 (de)
WO (1) WO2010061182A2 (de)
ZA (1) ZA201104635B (de)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8993789B2 (en) 2008-11-28 2015-03-31 Cipla Limited Process for preparing zanamivir and intermediates for use in the process
CN101962375B (zh) * 2010-09-21 2012-05-23 仙居县圃瑞药业有限公司 扎那米韦中间体叠氮还原工艺方法
WO2012114350A1 (en) 2011-02-24 2012-08-30 Cadila Healthcare Limited Process for the preparation of zanamivir
GB201106095D0 (en) 2011-04-11 2011-05-25 Glycom As N-Substituted mannosamine derivatives, process for their preparation and use thereof
DE102011117128A1 (de) * 2011-10-28 2013-05-02 Christian-Albrechts-Universität Zu Kiel Verbindungen zur Therapie der Influenza
WO2015032357A1 (zh) * 2013-09-09 2015-03-12 中国科学院上海有机化学研究所 扎那米韦和拉那米韦的中间体及其合成方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SK282950B6 (sk) 1990-04-24 2003-01-09 Biota Scientific Management Pty Ltd Deriváty alfa-D-neuramínovej kyseliny, spôsob ich prípravy, ich použitie a farmaceutické prípravky na ich báze
AU659501B2 (en) 1991-10-23 1995-05-18 Biota Scientific Management Pty Ltd Antiviral 4-substituted-2-deoxy-2,3-didehydro-derivatives of alpha-D-neuraminic acid
GB9126725D0 (en) 1991-12-17 1992-02-12 Glaxo Group Ltd Process
GB9220327D0 (en) 1992-09-25 1992-11-11 Glaxo Group Ltd Process
GB9220241D0 (en) 1992-09-25 1992-11-11 Glaxo Group Ltd Process
PT823428E (pt) * 1996-07-22 2002-04-29 Sankyo Co Derivados do acido neuraminico sua preparacao e sua utilizacao em medicina
US8993789B2 (en) 2008-11-28 2015-03-31 Cipla Limited Process for preparing zanamivir and intermediates for use in the process

Also Published As

Publication number Publication date
US20110257418A1 (en) 2011-10-20
ES2507492T3 (es) 2014-10-15
JP2012510456A (ja) 2012-05-10
EP2358695A2 (de) 2011-08-24
WO2010061182A3 (en) 2010-07-22
ZA201104635B (en) 2012-10-31
US8993789B2 (en) 2015-03-31
WO2010061182A2 (en) 2010-06-03
EP2476675A1 (de) 2012-07-18
KR20110098760A (ko) 2011-09-01
AU2009321347A1 (en) 2010-06-03
CA2744793A1 (en) 2010-06-03

Similar Documents

Publication Publication Date Title
EP2358695B1 (de) Verfahren zur herstellung von zanamivir und zwischenprodukte zur verwendung in dem verfahren
AU738577B2 (en) Preparation of cyclohexene carboxylate derivatives
US9981984B2 (en) Method for producing cis-5-hydroxy-2-piperidinecarboxylic acid derivative, and method for purifying cis-5-hydroxy-2-piperidinecarboxylic acid
CN113024396A (zh) 一种奥司他韦的制备方法及其中间体
CN102477007A (zh) 一种制备s-n-保护基-氮杂环丁烷-2-羧酸的新方法
EP1063232A2 (de) Verfahren zur Herstellung von erythro 3-Amino-2-hydroxybuttersäurederivaten
CA2083108A1 (en) Process for the production of .alpha.-hydroxy-.beta.-aminocarboxylic acids
CN110204587B (zh) 一种奥贝胆酸的合成方法
WO2010119890A1 (ja) テトラヒドロピラン化合物の製造方法およびその中間体
WO1996036603A1 (fr) Procede ameliore pour preparer la 4-hydroxy-2-pyrrolidone
US20070077632A1 (en) Method for preparing (s)-indoline-2-carboxylic acid and (s)-indoline-2-carboxylic acid methyl ester using hydrolytic enzyme
KR20070048741A (ko) 디아릴사이클로알킬 유도체의 제조방법
US20140073804A1 (en) Process for the preparation of zanamivir
CN107304171A (zh) 一种奥司他韦的合成方法
CN104356155A (zh) 一种(s)-叔丁基二甲基硅氧基-戊二酸单酰胺的制备方法
CN115417794B (zh) 一种沙格列汀中间体的制备方法
JP2007191446A (ja) ビフェニルメチルヒダントイン化合物、その製造方法、及びそれを用いるビフェニルアラニン化合物の製造方法
KR20090118557A (ko) ＨＭＧ-ＣｏＡ 환원 저해제의 제조를 위한 키랄 중간체의제조방법
US20240199530A1 (en) Industrial synthesis of serinol
US5502253A (en) Cyclohex-2-enyl acetamides
KR20090085445A (ko) 4-카르바모일-1-β-Ｄ-리보푸라노실이미다졸륨-5-올레이트의 생산을 위한 중간체로서의 2-아미노말론아미드의제조방법
KR20150095970A (ko) 오셀타미비어의 개선된 제조방법
CN118164877A (zh) 一种西司他丁钠中间体化合物
KR100958678B1 (ko) 시스-디메크로틴산 및 이의 염의 제조방법
CN113880723A (zh) 一种盐酸甜菜碱的制备方法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110520

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20120615

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20140211

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: AT

Ref legal event code: REF

Ref document number: 675860

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140715

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009025105

Country of ref document: DE

Effective date: 20140814

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: CIPLA LIMITED

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2507492

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20141015

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 675860

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140702

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20140702

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141003

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141103

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141002

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141002

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141102

REG Reference to a national code

Ref country code: DE

Ref legal event code: R082

Ref document number: 602009025105

Country of ref document: DE

Representative=s name: PATENTANWAELTE LIPPERT, STACHOW & PARTNER, DE

Ref country code: DE

Ref legal event code: R082

Ref document number: 602009025105

Country of ref document: DE

Representative=s name: LIPPERT STACHOW PATENTANWAELTE RECHTSANWAELTE , DE

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009025105

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20150407

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141124

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141130

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141130

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141130

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20151118

Year of fee payment: 7

Ref country code: IT

Payment date: 20151124

Year of fee payment: 7

Ref country code: GB

Payment date: 20151118

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20151014

Year of fee payment: 7

Ref country code: FR

Payment date: 20151008

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20091124

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602009025105

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20161124

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20170731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161124

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161130

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170601

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20161125

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20140702

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20181116